The present invention relates to a method for the preparation of the well known anti-depressant drug citalopram, 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1, 3-dihydro-5-isobenzofurancarbonitrile.
Citalopram is a well-known antidepressant drug that has now been on the market for some years and has the following structure: 
It is a selective, centrally acting serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, having antidepressant activities. The antidepressant activity of the compound has been reported in several publications, e.g. J. Hyttel, Prog. Neuro-Psychopharmacol. and Biol. Psychiat., 1982, 6, 277-295 and A. Gravem, Acta Psychiatr. Scand., 1987, 75, 478-486. The compound has also been disclosed to show effects in the treatment of dementia and cerebrovascular disorders, EP-A 474580.
Citalopram was first disclosed in DE 2,657,271 corresponding to U.S. Pat. No. 4,136,193. This patent publication describes the preparation of citalopram by one method and outlines a further method that may be used for preparing citalopram.
According to the process described, the corresponding 1-(4-fluorophenyl)-1, 3-dihydro-5-isobenzofurancarbonitrile is reacted with 3-(N,N-dimethylamino)propyl-chloride in the presence of methylsulfinylmethide as condensing agent. The starting material was prepared from the corresponding 5-bromo derivative by reaction with cuprous cyanide.
According to the second method, which is only outlined in general terms, citalopram may be obtained by ring closure of the compound: 
in the presence of a dehydrating agent and subsequent exchange of the 5-bromo group with cyano using cuprous cyanide. The starting material of formula II is obtained from 5-bromophthalide by two successive Grignard reactions, i.e. with 4-fluorophenyl magnesium chloride and N,N-dimethylaminopropyl magnesium chloride, respectively.
A new and surprising method and an intermediate for the preparation of citalopram were described in U.S. Pat. No. 4,650,884 according to which an intermediate of the formula 
is subjected to a ring closure reaction by dehydration with strong sulfuric acid in order to obtain citalopram. The intermediate of formula III was prepared from 5-cyanophthalide by two successive Grignard reactions, i.e. with 4-fluorophenyl magnesium halogenide and N,N-dimethylaminopropyl magnesium halogenide, respectively.
Further processes are disclosed in International patent application Nos. WO 98/019511, WO 98/019512 and WO 98/019513. WO 98/019512 and WO 98/019513 relate to methods wherein a 5-amino-, 5-carboxy- or 5-(sec. ammocarbonyl)phthalide is subjected to two successive Grignard reactions, ring closure and conversion of the resulting 1,3-dihydroisobenzofuran derivative to the corresponding 5-cyano compound, i.e. citalopram. International patent application No. WO 98/019511 discloses a process for the manufacture of citalopram wherein a (4-substituted-2-hydroxymethylphenyl-(4-fluorphenyl)methanol compound is subjected to ring closure and the resulting 5-substituted 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran converted to the corresponding 5-cyano derivative and alkylated with a (3-dimethylamino)propylhalogenide in order to obtain citalopram.
Finally, methods of preparing the individual enantiomers of citalopram are disclosed in U.S. Pat. No. 4,943,590 from which it also appears that the ring closure of the intermediate of formula III may be carried out via a labile ester with a base.
It has now been found that citalopram may be obtained by a new process in which the citalopram skeleton is formed by Diels-Adler reaction of a dihydrobenzofurane with a diene.
Accordingly, the present invention relates to a novel method for the preparation of citalopram, its enantiomers and acid addition salts thereof comprising:
Reaction of a compound of formula 
with
a) a diene having the formula III 
wherein X is selected from O, S, SO2, xe2x80x94Nxe2x95x90Nxe2x80x94, xe2x80x94COxe2x80x94Oxe2x80x94 and xe2x80x94Oxe2x80x94COxe2x80x94, followed by oxidation to form citalopram,
or with
b) a compound of formula 
wherein R is alkyl, or optionally substituted aryl or arylalkyl, followed by conversion of the resulting compound of formula 
wherein R is as defined above to a compound of formula 
which is converted to a compound of formula 
followed by oxidation of the compound of formula VII to form citalopram.
The reaction of the compound of formula II with the diene of formula III is carried out using the conventional reaction conditions for carrying out reactions of the Diels-Adler type. Thus, the reaction is suitably carried out in a solvent, such as benzene, toluene, 1, 3,5-trimethylbenzene; at a temperature between 60 and 180xc2x0 C., preferably at reflux.
Initial reaction of the compound of formula II with the diene of formula III leads to the formation of the intermediate having the formula 
wherein X is as defined above.
Oxidation of the intermediate of formula IIxe2x80x2 leads to the formation of citalopram.
The oxidation of the intermediate of formula IIxe2x80x2 is carried out in presence of oxygen and agents such as Pd/C, S, dideoxyquinon, and chloranil.
In some cases, i.e. where the compound of formula III is a 3-cyanofuran, the conversion of the intermediate of formula IIxe2x80x2 to citalopram is carried out in presence of a Lewis acid or a mineral acid. Suitable Lewis acids include ZnCl2, TiCl4, BF3 Et2O etc. Suitable mineral acids include hydrochloric acid, sulfuric acid etc.
When the compound of formula III used in the process is the 3-cyanofuran, the intermediate of formula IIxe2x80x2 may be isolated.
The reaction of the compound of formula II with the compound of formula IV is carried out using the conventional reaction conditions for carrying out reactions of the Diels-Adler type. Thus, the reaction is suitably carried out in an inert solvent, such as benzene, toluene, 1, 3,5-trimethylbenzene; at a temperature between 60 and 180xc2x0 C., preferably at reflux. The aryl and arylalkyl substituents R in formula IV may be substituted with substituents such as halogen, alkyl, alkoxy, etc.
The conversion of the compound of formula V to a compound of formula VI is suitably carried out in an aqueous acidic media or in an aqueous alkaline media.
The introduction of the cyano group into the compound of formula VI, is suitably carried out by reaction of a compound of formula VI with NaCN, KCN, or TMSCN in an aqueous media followed by dehydration using conventional dehydrating agents such as thionylchloride, POCl3, P2O5 or a Vilsmeier reagent. When TMSCN is used, the reaction is suitably carried out in presence of a Lewis acid such as ZnCl2, ZnI2 or BF3, Et2O.
The compound of formula VII is oxidised to form citalopram in presence of oxygen and agents such as Pd/C, dideoxyquinon, chloranil etc.
In a further aspect, the invention relates to the above processes in which the compound of formula II is used in the form of the S-enantiomer.
In yet another aspect, the present invention relates to citalopram and S-citalopram manufactured by the process of the invention, and an antidepressant pharmaceutical composition comprising citalopram or S-citalopram manufactured by the process of the invention.